This is a competitive renewal for an RO1 to apply mixed bone marrow chimerism to induce tolerance for primarily vascularized allografts. The applicants propose to continue their studies to apply mixed chimerism, with all of its advantages, to induce donor specific transplantation tolerance for solid organ allografts and to identify factors that will enable clinical application of this model. They will focus on three specific aims. The first aim is to achieve mixed chimerism with a nonlethal conditioning approach, since their current approaches require lethal recipient ablation, which cannot be justified in efforts to induce tolerance for solid organ grafts. The second aim is to define and characterize the host cell populations that constitute space (hematopoietic niche) and those that comprise alloresistance to engraftment in order to allow a specific approach to achieve chimerism and tolerance by targeting specific cellular populations in the host. The third specific aim is to examine whether chronic rejection of primarily vascularized allografts occurs or is prevented in mixed chimerism.